21-substituted thioacetals of 20-oxopregnanes and 20-oxo-pregnenes



Patented May 27, 1952 ZI-SUBSTITUTED THIOACETALS OF 20-OXO- PREGNANES AND 20-OXO-PREGNENES Albert Wettstein and Charles Meystre, Basel, Switzerland, assignors to Ciba Pharmaceutical Products, Inc., Summit, N. J.

No Drawing. Application July 10, 1950, Serial No. 173,001. In Switzerland July 22, 1949 6 Claims.

The present invention relates to zl-substituted thioacetals of the 20-oxo-pregnanes and 20-oxopregnenes and to the preparation thereof.

The conversion of ketones into'the corresponding acetals is a known reaction. It has also been repeatedly applied in steroid chemistry. Thus for example 3-, 7-, 12- or 20-oxo-pregnanes, as well as the corresponding pregnenes, which are unsubstituted in 21-position, can be converted without noteworthy difliculty into the corresponding acetals. However, it has not heretofore been possible to prepare the acetals of the 20-oxo-pregnanes and 20-oxo-pregnenes Which are substituted in the 2l-position.

A primary object of the present invention is the embodiment of acetals-and, more specifically, the thioacetals-of the aforesaid 2l-substituted 20-oxo-pregnanes and 2l-substituted 20-oxopregnenes and the development of a method for the preparation thereof.

It has been found, briefly stated, that by reacting the initial 21-substituted 20-oxo-pregnane or corresponding pregnene with a mercapto compound, more particularly an alkyl mercaptan, such as methyl mercaptan, ethyl mercaptan, benzyl mercaptan, ethylene dimercaptan and the like, in the presence of an acid catalyst such for example as hydrochloric acid, sulfuric acid or toluene-sulfonic acid, the desired thioacetal (mercaptol) of the starting compound is produced. It has further been found that the reaction takes place in most cases even at about C. It is preferable to work with an excess of the reactant mercaptan, which thus serves as the solvent medium. However, other diluents, such as the conventional organic solvents, can also be employed. The chemistry of the pregnane compounds, in particular that of the hormones of the suprarenal cortex, is thus enriched by a particularly valuable reaction. The so obtained thicacetals of 20-oxo-pregnanes and ZO-oxo-pregnenes, such as dialkylor diaralkyl-thioacetals, especially dimethyl-, diethy1-, dipropyl-, dibutylor dibenzyl-thioacetals are new compounds.

The 20-oxo-pregnanes and 20-oxo-pregnenes which serve as starting materials in the instant invention are substituted in the 21-position by a free or functionally converted hydroxyl group, for example an acyloxy group such as acetoxy, propionyloxy, benzoyloxy, or tosyloxy groups, or an alkoxy group such as a methoxy or ethoxy group, or by a halogen atom such as chlorine or bromine. They may also bear similar substituents or oxo groups in the 6-, 7-, 12- and in particular in the 3- and ll-positions, and they may bear epoxy groups, for example in the 3,9- and 16,17- positions. They can further have double bonds, for example in 3-, 4-, 5-, 11- and/or 16-position. also corresponding isomeric pregnane derivatives, for example pentacyclic i-pregnane, 17-iso-pregnane or allo-pregnane compounds, as well as the corresponding pregnenes may be used as starting materials.

The new products may be employed as therapeutic agents. They are however particularly valuable as intermediate products for the manufacture of therapeutically active compounds.

The following examples illustrate the invention, the parts being by weight unless otherwise stated and the relation between parts by weight and parts by volume being the same as that between the kilogram and the litre; temperatures are in degrees centigrade.

Example 1 3 parts A -3,21-diacetoxy-pregnene-20-one are covered with 10 parts by volume of carbon tetrachloride and 3 parts by volume of ethyl mercaptan and stirred using a calcium chloride moisture seal. Thereupon at 0, a slow stream of hydrogen chloride is passed over the liquid. After 2 hours stirring, the solution is concentrated in vacuum at 20. The oily residue is taken up in ether, the ethereal solution washed with dilute sodium carbonate solution and water, dried and evaporated. The oily reaction product is the A -3,2l-acetoxypregnene-20-one-diethy1-thioacetal of the formula JC-CHzO C OCH;

By carrying out the above reaction with benzyl mercaptan instead of ethyl mercaptan the A 3,2l-diacetoxy-pregnene 20 one-dibenzyl-thioacetal is obtained.

SCzHs CHaCOO Example 2 5 parts of A -3-hydroxy-2l-acetoxy-pregnene- 20-one are covered with 50 parts by volume of dioxane and 5 parts by volume of ethyl mercaptan. 2.5 parts of dehydrated calcium sulfate are added to the solution and then, while maintaining a calcium chloride moisture seal, hydroiS one-diethyl-thioacetal is superfluous.

the

of the formula CH3 CH3 By chromatographic purification over aluminum oxide, it can be obtained in the form of the pure oil. For most purposes, however, this operation In an analogous obtained. 7

' Example 3 2 parts of 3,2l-diaoetoxy-allo-pregnane-Zl)-one are covered with 5 parts by volume of ethyl mercaptan and parts by volume of chloroform. Thereupon, at while stirring and while mainmanner A -3-nydroxyr21- 1 acetoxy-pregnene-ZOFOne dibutyl thioaoetal is gen chloride is slowly passed over the liquid at v 1 0. 'After stirring for 10 hours, the calcium sulj fate is filtered oil with suction andthe filtrate evaporated in vacuum. The oily residue is taken 1 j'up mother, the ethereal solution washed with diulte sodium carbonate solution and water, dried j 1 and evaporated. 'The 1 oil, obtained as residue,

A -3-hydroxy-2l-acetoxy-pregnene-zo- Jew-1.00001 3; f V I termed;

taininga calcium. chloride moisture seal, a slow i stream of hydrogen chloride is passedover the liquid. 'After 18 hours, the solution is concentrated in vacuum. .The residue is taken 'up in ether, the ethereal solution is washed with dilute l sodium carbonate solution and water, dried and evaporated. The oil which remains behind contains the 3,21-diacetoxy-allo-pregnane-20-one diethyl-thioacetal of the formula c'mooo It may be directly used further, or maybe converted into the pure oily thioaoetal by chromatographic purification over aluminum oxide.

Example 4 5 parts of 3,21-dihydroxy-IZ-acetoXy-pregnane-ZO-one are dissolved in 5 parts by volume 5 of ethyl mercaptan; While stirring and mainr g r 2,598,653 7 taining a calcium chloride moisture seal, hydrogen chloride is then passed slowly over the liquid. After 10 hours, the solution is evaporated in vacuum, 1 the residue taken up in ether, the

ethereal solution washedwith dilute sodium carbonate solution and water,'dried and evaporated. The thus-obtained crude oily 3,2l-dihydroxy-12- acetQXyepregnane-ZO-one-diethyl-thioacetal the formula CHaCOO C2H5S $02115 can be purified by chromatography over aluminum oxide mreiera w after a tyl t r may be furtherused as the crud pr du t.

By replacin inthe above ex p e 1m ap anby methyl m rcaptan the 3.21-d hydroxy- I l2 -acetoxy-pregnane-20-dimethyl-thioaeetal is disclosed the invention, what is lower alkano'ic acid.

3. Lower dialkyl-thioacetals of M-ZO-oxO-pregnenes, which are substituted in the 2l-position by a member seleoted'from the group consisting ofa free hydroxyl group and a hydroxyl group esterified with a lower alka noio acid.

4., The A -3,21-diacetoxypregnene20-one-di- 1 ethyl-thieaeetal.

5. The A5-3-hydroxy-21-acetoXy-pregnene-20 one-dibutyl-thioacetal.

6. The 3,2l dihydroXy-12-acetoxy-pregnane- ZO-one-diethyl-tl1ioacetal.

; ALBERT WETTSTEIN.

CHARLES; MEYSTRE.

No references" cited. 

1. A LOWER DIALKYL-THIOACETAL SELECTED FROM THE GROUP CONSISTING OF THE LOWER DIALKYL-THIOACETALS OF THE 20-OXO-PREGNANES AND 20-OXO-PREGNENES, WHICH ARE SUBSTITUTED IN THE 21-POSITION BY A MEMBER SELECTED FROM THE GROUP CONSISTING OF A FREE HYDROXY GROUP AND A HYDROXYL GROUP ESTERIFIED WITH A LOWER ALKANOIC ACID. 